Advances in Process Spectroscopy: Mid-Infrared in-situ Reaction Monitoring Case Studies

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1 Advances in Process Spectroscopy: Mid-Infrared in-situ Reaction Monitoring Case Studies Product Reactant Intermediate Jeffrey W. Sherman, Ph.D. The Cortona Conference September 22, 2010

2 verview ReactIR as a PAT tool for the organic chemists Reaction analysis with ReactIR technology - Case study 1: Amide formation through mixed anhydride - Case study 2: Reductive Amination - Case study 3: N-acylation to amide (C-N formation) - Case study 4: Sandmeyer reaction - Case study 5: Rosenmund reduction (Hydrogenation) Questions and answers 1

3 ReactIR as a PAT Tool for the organic chemist Challenges of process chemistry - Did the reaction go? - Determine reaction kinetics - Understand reaction selectivity and reactivity - Identify intermediates, by-products and side products - Identify reaction end-points (intermediate and/or final product) - Impact on reaction with change of solvent, catalyst, temperature, etc. - Identify key design/control parameters - Determine early if the process scalable 2

4 Capabilities and advantages of ReactIR technology Continuous monitoring of: - Reaction components (reactant, intermediate, product, by-product, etc.) - Reaction progression (initiation, dynamics/rate, end-points, concentration, etc.) - Reaction kinetics, pathway, mechanism (fundamental understanding) 8For critical process parameters (boundary conditions, safety, control, etc.) 8For process efficiency and robustness (yield, productivity, reproducibility) 8For consistent product quality (purity, specs, variability, etc.) In situ real time analysis: - of components difficult to analyze otherwise -of 2 or H 2 sensitive or instable reaction mixtures - of highly toxic, hazardous or explosive reaction mixtures - at low/high temperatures and/or pressures - without perturbation, intrusion, material loss 3

5 Low Temperature Reactions-Anhydride and Amide R C Cl + R' C K R C C R ' R C C R ' + H 2 N R'' R''' C N R '' Monitoring bjective Develop in-depth knowledge of complex, low temperature reaction - identify key intermediates - develop method to track reaction species Improve performance of process for generic antibiotics - increase yield - reduce impurities; process cycle time Extend improvements to all antibiotic product lines 2010 Mettler-Toledo AutoChem, Inc.

6 Readily Track Acid Chloride Consumption and Critical Mixed Anhydride Formation Abs R C Cl R C C R Wavenumber Minutes 2010 Mettler-Toledo AutoChem, Inc.

7 Correlate Reaction Variables to Process Understanding R C C R Autoscaled Absorbance R C Cl End-point detection is critical for optimal product yield and purity Adjustment to the current hold time will result in production cost savings by reducing batch cycle time Minutes 2010 Mettler-Toledo AutoChem, Inc.

8 Refinements to Process Variables Enhances Production Efficiency 95.0 %Yield shortened hold time By controlling hold time, temperature, and feed rate, decomposition of critical anhydride intermediate was minimized verall yield improvement; less decomposition - better purity product ver $1M/yr improved profitability Batch Number 2010 Mettler-Toledo AutoChem, Inc.

9 In-Situ FTIR Monitoring of Nitrobenzene Hydrogenation N 2 NH 2 + H 2 Catalyst DMS Nitrobenzene Aniline Monitoring bjectives Track nitrobenzene consumption and aniline formation Determine effect of modifying catalyst (DMS) on reaction mechanism Define reaction end-point using aniline formation Eliminate oxygen contamination and hazards associated with grab sampling Reduce the dependency on time consuming and potentially hazardous grab sample analytical methods 2010 Mettler-Toledo AutoChem, Inc.

10 Readily Track Nitrobenzene Consumption and Aniline Formation aniline methanol Abs 0.25 water aniline nitrobenzene Wavenumber (cm -1 ) Hours 2010 Mettler-Toledo AutoChem, Inc.

11 Infrared Profiles Indicate Direct Conversion to Aniline Abs NH N Absence of DMS, which acts as a catalyst modifier, results in direct conversion to aniline. Reaction is complete in 2 hours Hours 2010 Mettler-Toledo AutoChem, Inc.

12 Infrared Profiles Suggest a Intermediate or Side Products Abs N NH Addition of DMS modifies catalyst selectivity, which causes an intermediate to form. The modifier extends the reaction time to greater than 5 hours Hours 2010 Mettler-Toledo AutoChem, Inc.

13 An Infrared Band for Aniline Reveals a Reaction Intermediate NH 2 Abs. Intermediate Hours Wavenumbers 2010 Mettler-Toledo AutoChem, Inc.

14 ConcIRT Extracts Reactive Intermediate Phenylhydroxylamine N 2 + H 2 Catalyst DMS NHH NH 2 PHA Relative Concentration nitrobenzene aniline Hours 2010 Mettler-Toledo AutoChem, Inc.

15 N-acylation to amide via acid chloride SCl 2 R Cl + S 2 + HCl R H PCl 5 R Cl + PCl 3 + HCl PCl 3 R Cl + H 3 P 3 Reactivity issues: - Reaction is fast so control is important - Toxic, hazardous chlorinating agents (worker exposure issue) - Gas evolution (scale-up issue) - Corrosive, acidic environment (worker exposure issue) 14

16 N-acylation to amide via acid chloride R1 H THF/DMF R2-NH 2 + SCl 2 60 C R1 Cl R1 N H R2 Process challenges - Accurate acid chloride end point determination - Process understanding to identify critical parameters - Understand reactivity - Monitoring with conventional offline techniques is challenging 8 Air-sensitive intermediate with decomposition issues 8 HPLC monitoring requires tedious derivative formation 15

17 N-acylation to amide via acid chloride R1 H THF/DMF R2-NH 2 + SCl 2 60 C R1 Cl R1 N H R2 Experimental procedure: - Stepwise additions in THF at RT of 8 RCH 8 DMF 8 SCl 2 - T increased and held at 60 C - Et 3 N addition (kills excess SCl 2 ) - Amine addition 16

18 N-acylation to amide via acid chloride R-CH 1726 cm -1 R-CCl 1782/1735 cm -1 Amide 1674 cm -1 SCl cm -1 17

19 N-acylation to amide via acid chloride Acid chloride SCl 2 Amide Acid N.B. Colthup, L.H. Daly and S.E. Wiberley, Introduction to Infrared and Raman Spectroscopy, 3rd Edition, Academic Press, San Diego, 1990, ISBN X George Socrates, Infrared and Raman Characteristics Group Frequencies Third Edition, John Wiley & Sons, 2002, ISBN

20 N-acylation to amide via acid chloride SCl 2 addition Amine addition RCH addition Reaction initiation Reaction endpoint Acid chloride Amide SCl 2 Acid Acid chloride is formed within 65 minutes after initiation Final amide is formed very rapidly (~2 minutes) upon amine addition 19

21 N-acylation to amide via acid chloride Summary ReactIR in situ data provided the following information: - SCl 2 accumulates in solution at room temperature - Heating initiates the reaction - Acid chloride forms in ~65 minutes - Acid chloride is stable at 60 C - Amide formation is very rapid (~2 minutes) ffline analysis may not be reliable: - Hydrolysis of intermediate acid chloride during sampling - Derivitization required potential errors 20

22 Sandmeyer Reaction X Y HBr, NaN 2 X Y CuBr, heat X Y + N 2 NH 2 N + N Br Br Aniline 'Diazonium salt' Aryl Bromide Process challenges: - Determine if the diazonium salt remains in solution until converted to the aryl bromide - Determine whether the diazonium salt is a well-behaved intermediate - Potentially explosive if the diazonium salt precipitates 21

23 Sandmeyer Reaction X Y HBr, NaN 2 X Y NH 2 N + N Br Aniline 'Diazonium salt' Heat flow (watts) NaN 2 add'n Absorbance (normalized) Time (hrs) Heat flow Diazo Sym etrical Ar-N2 1586cm-1 Aniline sym NH cm-1 Aniline reacts to cleanly form diazonium intermediate Intermediate remains stable during hold 22

24 Sandmeyer Reaction X Y CuBr, heat X Y + N 2 N + N Br Br 'Diazonium salt' Aryl Bromide Heat flow (watts x 3) Absorbance (normalized) CuBr add'n ramp to 70 C Time (hrs) Gas evolution (ml/min) Heat flow Diazo Symmetrical Ar-N2 1586cm-1 Product ArBr1097cm-1 Gas evolution Diazonium intermediate reacts to aryl bromide product ReactIR profiles indicate a possible intermediate exists 23

25 Sandmeyer Reaction X Y CuBr, heat X Y + N 2 N + N Br Br 'Diazonium salt' Aryl Bromide Absorbance (normalized) CuBr add'n ramp to 70 C Time (hrs) Diazo Sym m etrical Ar-N2 1586cm-1 Interm ediate 1258cm-1 Product ArBr1097cm-1 ReactIR data defines an aryl radical intermediate is formed Intermediate gives insight into reaction mechanism 24

26 Sandmeyer Reaction X Y CuBr, heat X Y + N 2 N + N Br Br Cu(I) -N 2 Cu(I) Cu(II) Cu(II) X C Y ++ Cu +2 2Br - Advanced rganic Chemistry Jerry March 4 th Edition ReactIR data confirms an aryl radical intermediate is formed 25

27 Sandmeyer Reaction Summary ReactIR showed that the diazonium salt remains in solution and is a wellbehaved intermediate - Allowed for safe scale-up of this chemistry ReactIR detemined the endpoint of the diazonium intermediate step ReactIR gave insight into the proposed mechanism of the Sandmeyer reaction - Identified aryl radical intermediate 26

28 Rosenmund reduction CH 2 C N C Cl H 2, Pd/C DIEA, thioanisole, toluene For a growth hormone secretagogue cbz N C H cbz N N Impurity H Process challenges: - Slow and incomplete conversion ( overnight), even with additional catalyst - Wide variation of yield: 50~96%, with formation of a dimeric impurity Merck: J. Wang, K. Rossen, J. Kukura, F. Gortsema, J. Sager, P.J. Pye, C.J. rella, and Y.-K. Sun, Merck & Co., Inc., Rahway, NJ, Kinetic and Pathway Analysis of Rosenmund Reduction of N-cbz-Isonipecotic Acid Chloride, 4th International Conference on rganic Process Research & Development, Hong Kong, March 18-21,

29 Rosenmund reduction Apparent incomplete conversion observed across a wide range of conditions Anhydride formation due to H 2 intrusion yield Y = X RCCl H 2 RCCl + RCH t-amine 4 2 RCCR ( % ) Acid not counted in yield calculation Not detected by HPLC assay 28

30 Rosenmund reduction HPLC assay sees no acidic anhydride n R-C-NHR NH 2 R n NH 2 R HPLC assay t-amine R-CH + R-CCl R-C--C-R + t-amine. HCl n 100 n R-CH (100-n) H 2, Pd/C, PhSMe, t-amine, 20C 0 0 Hydrogenation 29

31 Rosenmund reduction Anhydride formation confirmed by ReactIR Anhydride 1815 cm -1 Acid Chloride 1795 cm -1 Anhydride 1745 cm -1 Aldehyde 1725 cm -1 Inject H 2 ConcIRT H 2 on acid chloride aldehyde Reaction conditions: 0.1 anhydride 20 o C, 40 psig H 2, 350 ml (in a 1L vessel), 1000 rpm, DIEA:Substrate=1.25, 4.1 g-cat, 7.2 mg thioanisole/g-cat (>L c ) Time (min)

32 Rosenmund reduction Effect of anhydride on dimer formation without PhSMe (catalyst modifier) Conversion of Acid-Cl ( % ) Anhydride:AcidCl = 16:100 Anhydride:AcidCl = 1.5:100 [1 - exp(-0.06t)]*100 Yield to Products ( % ) Anhydride:AcidCl = 16:100 Anhydride:AcidCl = 16:100 Anhydride:AcidCl = 1.5:100 Anhydride:AcidCl = 1.5:100 Aldehyde Dimer Time ( hr ) Conversion of Acid-Cl ( % ) more Anhydride more Dimer less Aldehyde Two kinetic regimes: 1) Acid-Cl Aldehyde 2) Anhydride + Aldehyde Dimer 31

33 Rosenmund reduction Summary ffline analysis by HPLC failed to detect: - RCCR, a key by-product - The inertness of RCCR, cause of incomplete conversion ReactIR revealed RCCR formation and its inertness to reduction: - The key to incomplete conversion - The cause of formation of dimer impurity - The key to poor selectivity, low and inconsistent yield ReactIR monitoring of the reaction in real time without sampling helped to gain fundamental understanding of the process problem, and to develop a robust high yielding process 32

34 Case study 4: N-Substitution via reductive amination R 1 R' 1 + 2H R 1 C + H N -H 2 HC N R 2 R' 2 R 2 R' 1 R' 2 +2H R 1 CHH R 2 R 1 H C N R 2 +H - -H - R' 1 R' 2 +2H -H 2 ver reduction Need to know ER timely Need optimization R 1 C R 1 N R' 1 R' 2 Unstable Difficult to analyze offline Special care for storage Dimer(s) 33

35 ReactIR as a PAT tool for the organic chemist Successful and fast development and scale-up: - Monitor and control in real time from bench scale to pilot scale - Gain insight into root causes of process problems - Change or optimize existing process for robust performance - Design better processes for the future - Gain chemical specific and information rich data which provides 8Information on selectivity and reactivity 8Identification of intermediates, by-products and side products 8Pin-point end of reaction for intermediates or final product - Record, observe, analyze detailed changes from batch to batch 8Catch differences throughout reaction between batches 8btain critical information difficult to have otherwise Mettler-Toledo AutoChem, Inc.

36 Acknowledgements We would like to thank the following contributors: Bob Cooley - GlaxoSmithKline - Real-time Analytics User Forum - February 2005, NYC - USA Teva BioCraft, St. Louis, M Claude Didierjean, Ph.D. - METTLER TLED Will Kowalchyk, Ph.D. - METTLER TLED Jennifer Andrews, Ph.D. METTLER TLED Mettler-Toledo AutoChem, Inc.

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