1. Kinetics of a SnAr
Reaction
Robert Woodward – DynoChem User Meeting May 2011
2. Structure of talk
• Introduction to the chemistry
• The Iterative Dynochem Cycle
• Fitting the data
• Linear Free energy relationships
• Predictive chemistry
• Conclusions and summary
Simul
Optim.
(test )
2 Robert Woodward | May 2011 Dynochem User Meeting
3. The Chemistry
OH
F CN
F CN O
S
O MSP
O
F NMP, xylene
K2CO3 O
3 eq S
130oC SOLID
DFBN O
Monoaryl Sulfone
• First step in a manufacture of a diabetes medication
• High temperature reaction
• Solid / Liquid system – mass transfer may be important
• Large excess of difluoride required
3 Robert Woodward | May 2011 Dynochem User Meeting
4. The Problem....
• The sulfone requires high temperatures and long
heating periods to give significant conversion
• Upon extended heating times other impurities are
formed
• Impurities difficult to remove in downstream
processing
- CQA’s (cf Bernd Schmidt presentation)
• Does the use on another nucleophile mitigate against
some of these issues?
• Can other chemistry be developed in time to hit required
timelines?
4 Robert Woodward | May 2011 Dynochem User Meeting
5. Experiments
• 2 Substrates
- Sulfone
- Sulfide
Sulfone Sulfide
• 4 Temperatures
• 2 Base stoichiometries
• 2 Substrate concentrations
• 2 Dilutions
• Total of 10 experiments for each substrate
- 4 data points per experiment
- Each data point was a separate run
- Periodic repeats to assess reproducibility
• Experimental runs were carried out with speed of acquisition in mind
- CEM microwave – automated and rapid reactions
- Mettler-Toledo Flexiweigh gave fast and accurate automation
- LCMS for analysis
5 Robert Woodward | May 2011 Dynochem User Meeting
6. The Data 90
80
70
% Monoaryl
60
50 Monoaryl
40
30
20
10
0
0 500 1000 1500
Time (sec)
0.9
0.8
0.7
0.6
%Diaryl
0.5
0.4 Diaryl
0.3
0.2
0.1
0
0 500 1000 1500
Time (sec)
100
% Starting material
90
80
70
60
50 S.M.
40
30
20
0 500 1000 1500
Time (sec)
6 Robert Woodward | May 2011 Dynochem User Meeting
7. Data
The Dynochem Iterative Cycle
Simulate
Optimise
(test )
The Eyley Wheel
Robert Woodward | May 2011 Dynochem User Meeting
8. Kinetic Scheme
Keq O O
H K
OH O O
+ K2CO3 K
O O
S S
O O
F CN
O O
F CN k1
H K
O O
K + O
O
S F O
O S
O
F CN O CN
O O k2
H K O
O O S
K + O O O
O
S O O
O S S
O O
8 Robert Woodward | May 2011 Dynochem User Meeting
9. Kinetic scheme
Keq
Base + Phenol Reagent
k1
Reagent + Substrate Monoaryl + Byproduct
k2
Reagent + Mono Diaryl + Byproduct
9 Robert Woodward | May 2011 Dynochem User Meeting
10. Assumptions / Risks
• The mass-transfer rate of the solid K2CO3 is fast compared to the reaction
rate
• This remains the case throughout the reaction
• The heat-up / cool-down period is not taken into account – isothermal
conditions for the specified heating period is assumed.
• The intermediate complex between the phenol and the is reasonable under
the reaction conditions (Khalfina et al, Russ. J. Org. Chem., 2005, 41, 7, 978-
983)
- n.b. no formal deprotonation is required
10 Robert Woodward | May 2011 Dynochem User Meeting
11. Fitted data 60
120 C (exp)
50
120 C (calc) F CN
40 125 C (exp)
% Monoaryl
Monoaryl 30 125 C (calc)
130 C (exp) O
20
130 C (calc) O
10 135 C (exp) S
0 135 C (calc) O
0 500 1000 1500
Time (sec)
1.8 120 C (exp)
1.6
1.4
120 C (calc) O CN
1.2 125 C (exp) O
% Diaryl
1 S
Diaryl 0.8
125 C (calc)
O O
0.6 130 C (exp)
0.4 O
130 C (calc)
0.2 S
135 C (exp) O
0
0 500 1000 1500 135 C (calc)
Time (sec)
120 C (exp)
100
90 120 C (calc)
% Starting material
OH
80 125 C (exp)
S.M. 70 125 C (calc)
O
S
60 130 C (exp) O
50 130 C (calc)
40 135 C (exp)
0 500 1000 1500
135 C (calc)
11 Robert Woodward | May 2011 Time (sec) Dynochem User Meeting
12. Data fitted as a whole
100
90
80
70
60
Differing amounts
%
50
40 of base
30
20
10
0
0 500 1000 1500
Time (sec)
100
90
80
70
60
%
50
Differing dilutions
40
30
20
10
0
0 500 1000 1500
Time (sec)
12 Robert Woodward | May 2011 Dynochem User Meeting
14. That’s all well and good.....
F CN
F CN
O O F
H K F CN
O O -
K
O O
O F
S O
O S
O
SO2Me
• Mechanism explored – second order with a pre-equilibrium
• Exploration of Design Space
- Dynochem tools
• Reaction optimisation against downstream specification possible
- Control of impurities
- Understanding plant time requirements
14 Robert Woodward | May 2011 Dynochem User Meeting
15. What about any other nucleophiles? OH
σ (Substituent const.) O
S
0 0.2 0.4 0.6 0.8
Me
-6
-7
-8
Log(k) -9
-10
-11
-12
-13
-14
-15
Parameter Sulfoxide (predicted)
Keq (mol/L) 8 × 104
k1 (L/mol.s) 7.0 × 10-4
Ea1 (kJ/mol) 122
k2 (L/mol.s) 2.4 × 10-5
Ea2 (kJ/mol) 182
15 Robert Woodward | May 2011 Dynochem User Meeting
16. Sulfoxide Predictions
120
125 ºC
100
Monoaryl
80
%
60
40
Starting material
20
0
0 5 10 15 20 25
Time (min)
120
115 ºC
100
80
Starting material
%
60
40
Monoaryl
20
0
0 5 10 15 20 25
Time (min)
16 Robert Woodward | May 2011 Dynochem User Meeting
17. Conclusions
• Predictive model within the bounds of the experimental plan
• Kinetic data so can predict outside of this
- Reaction space within total knowledge base
• Fit for purpose at C3
- further experimentation required to de-risk any effect from
the solid base used (cf. assumptions)
• Predictivity extended to other nucleophiles for the reaction.
- Risks associated with LFERs
• Delivered specific knowledge base which enabled an
assessment of reactivity between sulfone and sulfide
• Gave greater confidence in manufacturing parameters
• Strategic work shows the validity of this type of approach and
facile, rapid generation of data from microwave kinetic
analysis. (No microwave effect)
17 Robert Woodward | May 2011 Dynochem User Meeting
18. What else could we have done?
100
90
80
70
60
%
50
40
30
20
10
0
0 2.5 5 7.5 10 12.5
Time (mins)
Parameter 1 Point Extended Study
Keq (mol/L) 1 × 105 1 × 105
k1 (L/mol.s) 1.4 × 10-5 ± 6 × 10-6 1.2 × 10-5 ± 6 × 10-6
Ea1 (kJ/mol) 122 ± 28 127 ± 20
k2 (L/mol.s) 2.4 × 10-6 ± 1 × 10-6 1.4 × 10-6 ± 8 × 10-7
Ea2 (kJ/mol) 133 ± 29 161 ± 26
18 Robert Woodward | May 2011 Dynochem User Meeting
19. Risk versus Effort
0.9
0.8
0.7
0.6
0.5
Risk
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12
Effort
• Profile of Effort / Risk will change with development stage
• Later stage development projects will require less risk
- Normally starting from a position from lower risk due to what
is “known” about the chemistry and process
19 Robert Woodward | May 2011 Dynochem User Meeting
20. Confidentiality Notice
This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and
remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or
disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2
6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, www.astrazeneca.com
20 Robert Woodward | May 2011 Dynochem User Meeting
