Article pubs.acs.org/OPRD
The Stability of N,N-Carbonyldiimidazole Toward Atmospheric Moisture Kenneth M. Engstrom,* Ahmad Sheikh, Raimundo Ho, and Robert W. Miller GPRD Process Research and Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States ABSTRACT: N,N-Carbonyldiimidazole (CDI) is known to be sensitive to degradation by atmospheric moisture. This work details some mechanistic aspects of CDI degradation by atmospheric moisture along with the major contributing factors to degradation rate. Also, several analytical techniques for the measurement of CDI purity that are less cumbersome than the traditional gas-capture assay are described.
■
INTRODUCTION N,N-Carbonyldiimidazole, commonly referred to as CDI, is most often used in chemical synthesis to convert a carboxylic acid functional group into a reactive acylating agent, particularly for the formation of amide bonds.1 CDI is widely used in the pharmaceutical industry for the preparation of both clinical candidates and in the manufacture of several marketed drugs.2 It is an attractive reagent for use on large scale because it is relatively inexpensive, safe, and commercially available. Also, the carbon dioxide and imidazole reaction byproducts resulting from its use are innocuous and readily purged from process streams. CDI can be prepared via reaction of 4 equiv imidazole with 1 equiv phosgene in THF.3 The hygroscopic imidazole hydrochloride reaction byproduct is removed via filtration. CDI is then isolated from the filtrate via crystallization by evaporation of the solvent and/or use of a nonpolar antisolvent. Several notes in the synthetic procedure hint that CDI is sensitive to atmospheric moisture, although no data quantifying this sensitivity is provided. Recently, we experienced a significant drop in efficiency of acyl imidazolide formation in a CDI-mediated amide bondforming reaction at scale during transfer of the process from our development facilities to the commercial manufacturing site. Circumstantial evidence suggested degradation of CDI during charging by atmospheric moisture to form imidazole and carbon dioxide as one potential cause. This work details our attempt to quantify the major contributing factors to the degradation rate of CDI on exposure to atmospheric moisture. This work, enabled by our development of several analytical techniques for the measurement of CDI purity, led us to a partial understanding of some of the mechanistic aspects of CDI degradation, along with discovery of CDI attributes which determine the relative degradation rates of individual lots of CDI. This knowledge has practical implications regarding the effective use of CDI in a manufacturing setting and may enable more efficient processes by others using CDI at manufacturing scale.
■
followed over time. The traditional method for assaying the purity of CDI involves measuring the amount of carbon dioxide evolved on hydrolysis.4 Development of other more convenient methods was pursued and resulted in development of distinct 1 H NMR- and HPLC-based assays. The HPLC-based assay utilizes derivatization of CDI with benzyl alcohol as shown in Scheme 1, followed by quantitation of dibenzyl carbonate in the Scheme 1. Quantitation of CDI through derivatization with benzyl alcohol
reaction mixture using a purchased dibenzyl carbonate standard.5 In our case, direct quantitation through 1H NMR was more expedient. Degradation Rates and Mechanistic Considerations. The purity, water content, and weight loss of samples of CDI exposed to 35% relative humidity at 22 °C were followed over 8 h. The degradation rate as measured by 1H NMR appears to follow zero-order kinetics, suggesting that CDI itself is not involved in the rate-determining degradation step (Figure 1). Additionally, the water content of the material as measured by Karl Fischer titration remained constant at 0.03 wt % (roughly 0.003 equiv) throughout the experiment, implying that any water adsorbing onto the solids was reacting immediately. Finally, the degradation rate as measured from sample weight loss closely matches that determined by 1H NMR, suggesting that release of carbon dioxide also follows zero-order kinetics and is not involved in the rate-determining degradation step. Interestingly, after 24 h the final CDI sample from the experiment in Figure 1 contained no detectable CDI by 1H NMR assay and 0.3% CDI according to weight loss. This result demonstrates that the initial CDI content of a lot may be measured simply from total sample weight loss after full degradation. Although this weight loss assay does not provide a purity determination as quickly as the 1H NMR- and HPLC-
RESULTS AND DISCUSSION
Analytical Methods. We first determined how the degradation of CDI to imidazole and carbon dioxide could be © 2014 American Chemical Society
Received: October 9, 2013 Published: March 28, 2014 488
dx.doi.org/10.1021/op400281h | Org. Process Res. Dev. 2014, 18, 488−494
Organic Process Research & Development
Article
Figure 1. Degradation of CDI with time at 35% RH and 22 °C.
Figure 2. Degradation rate of CDI with variable relative humidity.
based assays, its simplicity and accuracy should make it an attractive method for measurement of CDI purity. Experiments were carried out on the same lot of CDI under conditions in which the amount of atmospheric moisture (i.e., water concentration) supplied to react with the CDI samples was varied. In the first experiment, measurement of the degradation rate at different relative humidities was performed. As shown in Figure 2, an increase in relative humidity increased degradation rate. In a second experiment, measurement of the degradation rate with variable air flow was performed. As shown in Figure 3, an increase in air flow increased degradation rate. In the final experiment, measurement of the degradation rate for a constant mass of material with variable exposed surface was performed by placing the same amount of CDI in separate circular containers of variable diameter. As shown in
Figure 4, an increase in exposed surface increased degradation rate. In all cases the rate of degradation increases when the variables related to exposure of CDI to atmospheric moisture are increased, suggesting water is involved in the ratedetermining step of CDI degradation. In order to further understand the degradation reaction pathway, an attempt was made to follow the transformation of CDI to imidazole through single-crystal X-ray diffraction by exposing a crystal of CDI to a controlled RH environment over time. However, no intermediate structures were detected through changes in cell parameters, and at the end of the experiment parameters consistent with those of imidazole were calculated. SEM images of the samples before and after degradation shown in Figure 5 reveal substantial reduction in particle size and deterioration in morphology. Crystal structure 489
dx.doi.org/10.1021/op400281h | Org. Process Res. Dev. 2014, 18, 488−494
Organic Process Research & Development
Article
Figure 3. Degradation rate of CDI with variable air flow.
Figure 4. Degradation rate of CDI with variable exposed surface.
However, as shown in Table 2, no direct relationship between specific surface area and degradation rate was found. Therefore, counter to expectations, specific surface area is not the sole variable which determines the relative degradation rates of different lots of CDI. The process for CDI manufacture involves filtration to remove imidazole hydrochloride. We suspected that variability in removal of this byproduct and its incorporation into the CDI batch could also contribute to the difference in degradation rate, given that imidazole hydrochloride is hygroscopic and is also known to increase the reactivity of acyl imidazolides.6 As shown in Table 2, inclusion of the chloride content of each lot as measured by ion chromatography allows for explanation of the trends in relative degradation rates. For example, even though CDI lot 1 has specific surface area similar to that of CDI lot 2, its relatively low chloride content results in a slower degradation rate. Also, even though the specific surface area of CDI lot 4 is three times less than that of CDI lot 5, its
descriptors in Table 1 reveal that the true density value of imidazole crystals is greater than that of CDI crystals, primarily because of the H-bonding interactions that exist in the former (Figure 6). The increase in true density helps explains breakage and deterioration in morphology. Lot-to-Lot Degradation Rate Variability. The studies detailed above were all performed using the same lot of CDI. However, we observed that different lots of CDI had variable degradation rates under the same conditions as shown in Table 2. All lots of CDI displayed similar melting points of 118−122 °C and the same pattern by PXRD analysis, indicating the crystal form was not the source of degradation rate variability. Specific surface area is also a variable likely to impact degradation rate, as the amount of exposed surface is likely to increase the kinetics of moisture uptake. As surface area is inversely related to the particle size, the particle size distribution (PSD) was measured, and the data were used to estimate the specific surface area of the different CDI lots. 490
dx.doi.org/10.1021/op400281h | Org. Process Res. Dev. 2014, 18, 488−494
Organic Process Research & Development
Article
Figure 5. (a) SEM image of starting CDI particles; (b) SEM image of imidazole particles obtained after complete CDI degradation.
Table 1. Crystal lattice parameters for CDI and imidazole space group a, Å b, Å c, Å α, deg β, deg γ, deg Z volume Å3 density g/cm3
CDI
imidazole
P1̅ 5.781 7.27 18.13 78.9 87.43 73.798 4 717.983 1.107
P21/n 7.604 5.382 9.056 90 108.876 90 4 350.748 1.289
degradation rate is similar due to relatively high chloride content. To establish the relative importance of the CDI particle size (or surface area) and chloride content to the degradation rate, a chemometric model was developed on the basis of the partial least-squares (PLS) method. PLS was employed here due to its effectiveness in projecting highly correlated dimensional data matrices into low dimensional subspace while providing good estimates on the response. The input variables for PLS are the cumulative PSD at 10%, 50%, and 90% volume basis (Dv10, Dv50 and Dv90) and chloride content. A two-component PLS model was found to give the minimum root mean predicted residual sum of squares (root mean PRESS) whilst providing a good R2 of 0.9711 (R2 is the fraction of the cumulative sum of squares of response explained by the model fit) (Figure 7). As shown from the model coefficients in Figure 8, chloride content has a positive correlation with degradation rate and is the most sensitive variable. All PSD numbers have a negative correlation with degradation rate, confirming that the kinetics of moisture uptake/exchange is increased by a higher specific surface area. From the variable importance for projection (VIP) plot, all variables have values close to or above 0.8, confirming that
Figure 6. (a) CDI unit cell showing no H-bonding network, (b) imidazole structure with H-bonded chains.
these variables are important to the degradation rate of CDI.7 The capability of estimating the CDI degradation rate simply by using PSD and chloride content provides practical utility in estimating degradation reaction kinetics for any lot of CDI. Practical Implications. On the basis of our findings, we analyzed various lots of CDI purchased from several vendors.8 Alarmingly, multiple unopened drums of CDI whose certificates of analysis claimed greater than 97% purity contained material of only 50−80% purity, presumably due to degradation. We did note that two of these drums with the same vendor lot number had degraded to differing extents. This suggests that the packaging of CDI in the individual drums by vendors needs to be done appropriately to ensure the material does not degrade during packaging, transport, or storage. 491
dx.doi.org/10.1021/op400281h | Org. Process Res. Dev. 2014, 18, 488−494
Organic Process Research & Development
Article
Table 2. Degradation rates, PSD, and chloride content of various lots of CDI CDI lot
degradation rate (%/h)
Dv10 (μm)
Dv50 (μm)
Dv90 (μm)
PSD span
specific surface area estimated from PSD (m2/g)
chloride content (w/w%)
1 2 3 4 5
8.0 12.7 12.7 17.0 18.3
52 60 66 58 19
155 180 219 188 67
517 595 479 428 212
3.00 2.97 1.89 1.97 2.88
0.047 0.041 0.035 0.041 0.124
0.02 0.09 0.07 0.12 0.03
Additionally, several lots of CDI known to be of acceptable quality at the time of their initial use in several of our processes had also partially degraded on storage. This suggests that resealing of the packaging can be critical if the same batch of CDI is to be used multiple times. At lab scale, the existence of degradation of CDI by atmospheric moisture is of relatively low importance to the success or failure of a given reaction. Laboratory environments are, more often than not, well controlled with respect to humidity and air flow. In addition, there is usually not significant surface exposure during material dispensing, and reagent addition is generally carried out promptly. However, these factors can all change significantly when moving from the lab to a manufacturing environment. For example, the presence of blow out walls as part of the structural design of many processing suites containing manufacturing-scale reactors can lead to wide fluctuation in humidity, even within the same processing suite. Additionally, many processing suites operate at a high rate of air flow designed to limit buildup of dust and vapor which could result in an unsafe condition from both an operator exposure or explosion hazard perspective. Finally, many methods exist for charging a material from its container to the reactor. While addition directly to the reactor in a timely manner is certainly preferable as a charge method from the perspective of limiting the exposure of the CDI to atmospheric moisture, there are clearly situations where this is not viable. For example, some facilities may require use of secondary charge containers for additions of solids to reactors, which could result in significant exposure of the CDI surface to atmospheric moisture as the material is poured from its original container into the secondary charge container. Additionally, safety considerations may require charging of CDI using an inerted solids addition funnel. Given the limited capacity of most solids addition funnels, multiple charges of CDI to the solids addition funnel may be required, necessitating some forethought into how the contents of the CDI drum will be protected from atmospheric moisture during the charge time. All these factors indicate that degradation of CDI by atmospheric moisture should not be ignored in a manufacturing setting for processes in which a tight CDI operating range is required.
Figure 7. Relationship between experimental degradation rate and predicted degradation rate by PLS.
■
CONCLUSIONS Measurement of CDI degradation rate by HPLC, 1H NMR, and weight loss assays led to the determination that atmospheric moisture is involved in the rate-determining step of CDI degradation. As such, degradation rate increases with increasing humidity, air flow, and exposed surface. Additionally, particle size distribution and chloride content are the most critical variables that impact the relative degradation rates of different lots of CDI. These findings have practical implications with respect to the assay, packaging, and storage of CDI. With respect to charging of CDI in a manufacturing setting, these
Figure 8. Model coefficients of scaled and centered variables (Dv10, Dv50, Dv90, and chloride content) for the response (degradation rate) by PLS, and variable importance plot.
492
dx.doi.org/10.1021/op400281h | Org. Process Res. Dev. 2014, 18, 488−494
Organic Process Research & Development
Article
with vacuum grease to slow mixing of dessicator atmosphere with outside atmosphere. The dessicator contained a relative humidity meter and a saturated aqueous K2SO4 solution. At the time intervals shown in Figure 2, one dish was removed from the dessicator, the material in the dish mixed with a spatula, and the CDI purity measured by 1H NMR assay. The relative humidity was recorded every 5 min. Fluctuations in humidity in Figure 2 correspond to the opening and closing of the dessicator upon first adding and then sequentially removing samples. This experiment was repeated twice using the same CDI lot and experimental design, with the exceptions of the use of saturated aqueous NaCl and saturated aqueous LiCl solutions in place of the saturated aqueous K2SO4 solution. Degradation Rate of CDI with Variable Air Flow (Figure 3). To three different tared 45 mm diameter crystallizing dishes were added 4.00 g portions of CDI of 95.8% purity as measured by 1H NMR assay. The dishes were placed on the opening of a chemical fume hood with the emergency air flow activated. Measurement of the air flow by an air flow meter over several minutes showed an average air flow of 270 ft/min. At the time intervals shown in Figure 3, the material in one dish was mixed with a spatula and the CDI purity measured by 1H NMR assay. This experiment was repeated once using the same CDI lot and experimental design, with the exception of placement of the CDI dishes on the benchtop. Measurement of the air flow by an air flow meter over several minutes showed an average air flow of 0−5 ft/min. Degradation Rate of CDI with Variable Exposed Surface (Figure 4). To three different tared 45 mm diameter crystallizing dishes were added 8.00-g portions of CDI of 95.8% purity as measured by 1H NMR assay. The dishes were placed on the benchtop. At the time intervals shown in Figure 4, the material in one dish was mixed with a spatula and the CDI purity measured by 1H NMR assay. This experiment was repeated twice using the same CDI lot and experimental design, with the exceptions of use of 25 mm diameter vials and 75 mm diameter crystallizing dishes in place of the 45 mm diameter crystallizing dishes. Measurement of PSD of CDI. The PSDs of different CDI lots were measured by a laser diffraction technique using the Malvern Mastersizer 2000 coupled with the Hydro 2000S wet dispersion accessory (Malvern Instruments, Malvern, U.K.). Measurement conditions including the choice of dispersant/ surfactant combination, sample mass, stirrer/pump speed, obscuration concentration and measurement time were determined by conducting method development studies prior to actual data collection. Specific surface area values were estimated from the PSD with a CDI true density of 1.39 g/mL and the assumption of spherical particles. Measurement of Chloride in CDI. The w/w% chloride in CDI was determined by analysis of a sample diluted with 1:1 THF/water using the following ion chromatography method: Metrosep A Supp 7, 250 mm × 4.0 mm, 5 μm particle size with a Metrosep RP, 50 mm × 4.0 mm guard column, 0.7 mL/min, 23 °C, 20 μL injection volume, detection by conductivity with current of 50 mA and range of 50 μS/cm, isocratic aqueous 3.5 mM Na2CO3 and 1.0 mM NaHCO3 mobile phase for 15 min. Quantitation was accomplished by appropriate dilution of a purchased 1000 ppm chloride standard with 1:1 THF/water. Partial Least Squares Regression. PLS analysis was carried out in JMP (version 10, SAS, NC). The optimum
results indicate that precautions should be undertaken for minimization of moisture contact with the reagent and suggest that reaction completion assays may be critical to successful use of CDI at scale.
■
EXPERIMENTAL SECTION Assay of CDI by Derivatization to Dibenzyl Carbonate. A tared flask is charged with benzyl alcohol (approximately 10 equiv) and CDI (1 equiv) and heated to 80 °C for 30 min. The solution is cooled and weighed. CDI purity is equivalent to the reaction yield. Reaction yield is calculated using the w/w% dibenzyl carbonate in the reaction mixture and the reaction mass. The w/w% dibenzyl carbonate in the reaction mixture is determined by analysis of a sample diluted with MeCN using the following HPLC method: Supelco Acentis Express C18, 100 × 3.0 mm, 2.7 μm particle size, 0.8 mL/min, 45 °C, 5 μL injection volume, detection at 205 nm, 70:30 0.1 v/v% aqueous H3PO4:MeCN to 5:95 0.1 v/v% aqueous H3PO4:MeCN over 15 min. Quantitation was accomplished using a standard solution prepared by dissolving 13.9 mg purchased dibenzyl carbonate in 100 mL MeCN. Assay of CDI by 1H NMR Analysis. A tared vial is charged with approximately 0.7 mL of CDCl3 or d6-DMSO of known water content and then weighed. A known amount of CDI is then added to the vial and the 1H NMR spectrum acquired. CDI purity is calculated using the areas of the CDI (8.2, 7.5, and 7.2 ppm in CDCl3) and imidazole (7.7 and 7.1 ppm in CDCl3 peaks) with correction for the water content of the solvent. Decomposition of CDI with Time (Figure 1) and Assay of CDI by Weight Loss. To seven different tared 45 mm diameter crystallizing dishes were added 4.00 g portions of CDI of 93.9% purity as measured by 1H NMR assay. At the time intervals shown in Figure 1, one dish was weighed, the material in the dish mixed with a spatula, and the CDI purity measured by 1H NMR assay. For the final sample after 24 h, the dish was weighed, the material in the dish mixed with a spatula, and the CDI purity measured by 1H NMR assay was 0%. The initial purity of the CDI lot could be calculated from the total weight loss of this sample as shown below. 4.00 g initial sample − 3.40 g final sample = 0.60 g weight loss 0.60 g weight loss (28.01 g/mol for CO atoms lost − 2.02 g/mol for 2H atoms gained) = 0.023 mol gas lost
0.023 mol gas lost = 0.023 mol CDI in initial sample 0.023 mol CDI in initial sample × 162.15g/mol = 3.73 g CDI in initial sample
⎛ 3.73 g CDI in initial sample ⎞ ⎜ ⎟ × 100 = 93.2%purity 4.00 g initial sample ⎝ ⎠
Degradation Rate of CDI with Variable Relative Humidity (Figure 2). To three different tared 45 mm diameter crystallizing dishes were added 4.00-g portions of CDI of 95.8% purity as measured by 1H NMR assay. The dishes were placed in a glass dessicator with the seal coated 493
dx.doi.org/10.1021/op400281h | Org. Process Res. Dev. 2014, 18, 488−494
Organic Process Research & Development
Article
number of PLS components was selected by minimizing the root mean PRESS. All data from the input variables were mean centered and scaled to unit variance to eliminate the influence of any given variable with high variance on the model parameters.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS The work presented in the article was sponsored by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. Kenneth Engstrom, Ahmad Sheikh, Raimundo Ho, and Robert Miller are employees of AbbVie. The authors thank Paul Brackemeyer for collecting single-crystal X-ray data along with Michael Theine for the dispensing of numerous CDI samples from the chemical warehouse. The authors also thank colleagues involved in the transfer of processes to our commercial manufacturing facility, particularly Samrat Mukherjee and Rory Delaney, for valuable discussions surrounding CDI charging practices.
■
REFERENCES
(1) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. (2) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, T. W. Org. Biomol. Chem. 2006, 4, 2337. (b) Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Process Res. Dev. 2000, 4, 17. (3) (a) Staab, H. A. Leibigs Ann. Chem. 1957, 609, 75. (b) Staab, H. A.; Wendel, K. Org. Syntheses 1968, 48, 44. (4) Armstrong, A.; Li, W. N,N-Carbonyldiimidazole. In e-EROS: Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd: New York, 2007; 10.1002/9780470842898.rc024.pub2. (5) We anticipate quantification of the derivatization-based assay by GC would be successful, although we have not evaluated it specifically. (6) (a) Woodman, E. K.; Chaffey, J. G. K.; Hopes, P. A.; Hose, D. R. J.; Gilday, J. P. Org. Process Res. Dev. 2009, 13, 106. (b) We have observed that imidazolium triflate can accelerate the rate of reaction between an aliphatic carboxylic acid and CDI. It is possible that imidazolium hydrochloride similarly accelerates reaction between CDI and moisture. (7) Wold, S. PLS for Multivariate Linear Modeling 1994. In QSAR: Chemometric Methods in Molecular Design: Methods and Principles in Medicinal Chemistry; Wiley-VCH: New York, 1995. (8) At the time of this analysis, all vendors from which we purchased CDI were not the original manufacturers of the material.
494
dx.doi.org/10.1021/op400281h | Org. Process Res. Dev. 2014, 18, 488−494
