Article pubs.acs.org/OPRD
Safer Preparation of m-CPBA/DMF Solution in Pilot Plant Xingmin Zhang, Anjun Hu,* Chongfeng Pan, Qiwu Zhao, Xianwen Wang, and Jiang Lu Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co. Ltd., Changshu, Jiangsu 215537, China S Supporting Information *
ABSTRACT: The usage of m-CPBA (meta-chloroperbenzoic acid) is limited on large scale due to its thermal instability, although it is a good oxidant and well-accepted in laboratory scale. In our recent project, m-CPBA was used for an oxidation reaction, and an explosion hazard was identified. To ensure the safe use of m-CPBA on large scale, the stability of m-CPBA in different solvents was investigated, and it was found that besides the incompatibility between m-CPBA and DMF reported earlier, the intrinsic instability of m-CPBA/DCM solution at high concentration (low onset temperature and large exotherm) can also cause a major problem on large scale. Therefore, process parameters such as concentration of m-CPBA, addition sequence, and handling temperature have been investigated and successfully applied in pilot plant for a large scale reaction using 8 kg of mCPBA.
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INTRODUCTION One of the most important aims of process development is to develop an inherently safer process by effective hazard identification and process optimization to lower the corresponding risk and to avoid or eliminate the hazards at source, rather than relying on safety systems and procedures to manage risk.1 This paper reports an inherently safer process optimization using m-CPBA as an oxidant. m-CPBA is a common oxidant that is widely used in the laboratory for heteroatom oxidations and epoxidations.2 However, the safety concerns with its use on large scale are well-known, with the pure solid being shock-sensitive and potentially explosive in the condensed phase.3 In our recent project, m-CPBA was used for the transformation of thioether to sulfoxide and sulphone. An incompatibility hazard between m-CPBA and DMF that may cause severe explosions has been reported previously.4 As suggested in the literature, DCM could be a safer solvent for preparation of m-CPBA solution, but our investigations indicated that besides the incompatibility between m-CPBA and some solvents, the intrinsic instability of m-CPBA solutions at high concentration (low onset temperature and large exotherm) can pose a major problem on large scale. Therefore, it should be pointed out that DCM cannot be viewed as an inherently safer solvent for preparation of m-CPBA solutions, especially at high concentration. In the current research, a safer concentration of m-CPBA solution was defined. Other factors, such as the addition sequence and handling temperature, were also investigated and defined. mCPBA was successfully applied in pilot plant scale by strict implementation of the predefined safety measures.
stability of m-CPBA/DMF and m-CPBA/DCM mixtures at high concentration (1.1 g m-CPBA was added in 1 mL DMF or DCM, respectively). The comparative results are listed in Table 1, entries 1 and 2. (To make the results comparable, the heat Table 1. Stability of m-CPBA in different solventsa solvent
onset temp (°C)
heat release [J/(g mixture)]
heat release [J/(g m-CPBA)]b
1 2 3 4 5
DCM DMF DMAC acetone CH3CN
56 46 42 46 48
417 562 545 735 603
919 1045 1009 1259 1034
a
Tested on a RADEX instrument (Rapid Detection of Exothermic Reaction; for detailed information for this equipment please refer to the Experimental Section), scanning range 25−200 °C with heating rate of 0.5 °C/min. 0.1.1 g m-CPBA added in 1 mL of solvent. Be aware that the mixture is explosive, and preparation procedure in the experiment section should be strictly followed. bNormalized method: {heat release of m-CPBA mixture [J/(g mixture)]}/(mass concentration of m-CPBA). Taking m-CPBA/DCM solution as an example, the mass concentration of m-CPBA is 45.4%, so then the heat release in the unit of [J/(g m-CPBA)] is 417 [J/(g mixture)]/0.454 = 919 [J/ (g m-CPBA)].
release amount obtained from direct test with [J/(g mixture)] as unit in different solvents was normalized to the unit of [J/(g m-CPBA)], last column of Table 1.6) As can be seen from the normalized results, the decomposition energy of m-CPBA/ DCM solution is lower than that of m-CPBA/DMF solution, and the onset temperature is 10 °C lower, which can be explained by the incompatibility of m-CPBA and DMF reported by Kubota.4 However, it should also be noted that, at high mCPBA concentration, even without the incompatibility problem, DCM is not an inherently safer solvent for the
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RESULTS AND DISCUSSION Stability of m-CPBA in Different Solvents. In our original procedure, 11 g of m-CPBA (70%) was dissolved in 10 mL if DMF. The concentration of 1.1 g (m-CPBA)/mL(DMF) was in hazardous concentration range (in this range, after a short period of holding time, explosion will occur).4 As suggested in the literature, DCM could be a safer solvent for preparation of m-CPBA solutions.4 Therefore, we compared the © 2013 American Chemical Society
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Special Issue: Safety of Chemical Processes 13 Received: August 5, 2013 Published: October 15, 2013 1591
dx.doi.org/10.1021/op400208b | Org. Process Res. Dev. 2013, 17, 1591−1596
Organic Process Research & Development
Article
Figure 1. DSC scanning (test range 0−400 °C) of m-CPBA solid with heating rate of 4 °C/min
Figure 2. DSC scanning (test range 0−400 °C) of 1.1 g/mL m-CPBA/DMF solution
preparation of m-CPBA solution due to the intrinsic instability of m-CPBA (Figure 1). One may notice that the onset decomposition temperature of m-CPBA is 89 °C, which is much higher than the onset decomposition temperature of the m-CPBA/DCM solution. As reported in the literature,5 if decomposition happens right after melting, the actual
decomposition onset temperature could be much lower than the value directly shown in the differential scanning calorimetry (DSC) diagram in that the decomposition may already have begin but is masked by the melting event, i.e., the possible onset decomposition temperature is in the melting range. We also investigated the stability of various m-CPBA solutions with 1592
dx.doi.org/10.1021/op400208b | Org. Process Res. Dev. 2013, 17, 1591−1596
Organic Process Research & Development
Article
Figure 3. DSC scanning (test range 0−400 °C) of 0.13 g/mL m-CPBA/DMF solution (m-CPBA added first)
Figure 4. DSC scanning (test range 0−400 °C) of 0.13 g/mL m-CPBA/DMF solution (DMF added first)
in the literature,8 although the former (m-CPBA/acetone solution) is more stable. In all, at high concentration of m-CPBA, incompatibility may exist between m-CPBA and many solvents, such as DMF, DMAC (dimethylacetamide), acetone, CH3CN, etc., but for DCM, even without the incompatibility problem, high concentration of m-CPBA solution is not inherently safer due to the intrinsic instability of m-CPBA mentioned above. Our synthetic chemists explored the possibility of using DCM in place of DMF and found that more than 50% impurities appeared. The project team still decided to use DMF as a solvent, but the preparation of DMF solution required optimization. Optimization for Preparation of m-CPBA/DMF Solution. The next step is to optimize the preparation of mCPBA/DMF solution in a safer manner. The following factors
different solvents; test results are listed in Table 1, entries 3−5. As can been seen from Table 1, all solvents readily decompose at a relatively low temperature with high decomposition energy. Onset decomposition temperature of DCM solution is 56 °C, which is higher than that in other solvents. In the meantime, the normalized decomposition energy in DCM is lower than that in other solvents (Table 1, last column).6 In considering both the higher onset temperature and lower decomposition energy, DCM and m-CPBA are less likely to cause an incompatibility problem as reported.4 However, incompatibility between m-CPBA and other solvents cannot be excluded. Particular attention should be paid to the incompatibility between m-CPBA and acetone due to the possible formation of dimeric and trimeric cyclic peroxides that may pose devastating explosions,7 similar to the explosive mixture of H2O2, acetone, and sulphuric acid reported 1593
dx.doi.org/10.1021/op400208b | Org. Process Res. Dev. 2013, 17, 1591−1596
Organic Process Research & Development
Article
Figure 5. DSC iso test of 0.13 g/mL m-CPBA/DMF solution held for 16 h at 60 °C
Figure 6. DSC rescanning (test range 0−400 °C) after iso test of 0.13 g/mL m-CPBA/DMF solution at 60 °C
concentration may affect the stability of the m-CPBA solution. The effect of a different addition sequence for the preparation of m-CPBA solutions has not been reported previously in the literature. Relevant tests were performed to confirm our assumption. The comparative experiments were conducted at the same concentration: 0.13 g/mL DMF. Heat release of 163 J/g with the onset temperature of 36 °C was recorded with the addition of m-CPBA first followed by DMF (Figure 3). However, a significantly lower decomposition energy of 80 J/g was detected with the opposite addition sequence (Figure 4). Obviously, the addition of DMF followed by m-CPBA is safer.9 The apparently different outcome between the different addition orders can be attributed to the incompatibility of mCPBA and DMF as described in the literature.4 Definition of a Safer Operating Temperature. As can be seen from the above results, process safety has been greatly improved after reduction of the concentration and changing the order of addition of m-CPBA. Only 80 J/g heat release was measured during the DSC scanning test, which is equivalent to an adiabatic temperature rise of 40 °C (assume the specific heat capacity of DMF mixture is 2.0 J/g·K), and the boiling point of DMF cannot be reached. However, it was desirable to define a safer operating temperature range in which no decomposition of m-CPBA was observed. This is important as decomposition of m-CPBA will likely form more impurities (quality issue), and m-CPBA consumed by decomposition may affect the normal reaction. To avoid this scenario, isoperibolic tests have been conducted. Different from scanning tests (scan the fresh sample from 0 to 400 °C with 4 °C/min heating rate; onset temperature and total decomposition heat could be obtained), an isoperibolic test is to hold the sample at a predefined
were addressed: (1) reduction of the concentration of m-CPBA in DMF; (2) addition sequence of m-CPBA in DMF (this may have a great impact on the process safety; if m-CPBA is added first, the mixture will go through a high concentration at initial stage); and (3) definition of a safer operating temperature. Concentration. As can be seen from Figure 2, 798 J/g heat release was detected for the original m-CPBA/DMF sample (1.1 g/mL DMF), whereas 163 J/g of heat release was detected when the concentration was diluted to 0.13 g/mL DMF (Figure 3). With the dilution of the solution, the decomposition energy decreased accordingly. In the process, m-CPBA solution is added into the substrate solution in the reactor, and the reaction is addition-controlled (after the addition of m-CPBA solution is completed, the conversion rate is higher than 90%). After discussion, it was decided that the m-CPBA solution could be diluted to 0.13 g/ mL, while at the same time the concentration of substrate solution in the reactor increased. It should not pose a problem, because (1) the substrate is very stable, and (2) the following experiment confirmed that the reaction works well when adding diluted m-CPBA solution into substrate solution with increased concentration, thus leaving the overall reaction concentration unchanged. Subsequent experimentation confirmed that the reaction can work well under these modified conditions (still addition-controlled, > 90% conversion rate after completing addition). Addition Sequence. We assumed that the addition sequence might be another crucial factor for the preparation of m-CPBA/ DMF solution: if we add m-CPBA first followed by adding solvent, the mixture will experience an unstable high concentration stage, and some impurities formed at high 1594
dx.doi.org/10.1021/op400208b | Org. Process Res. Dev. 2013, 17, 1591−1596
Organic Process Research & Development
Article
Figure 7. DSC iso test of 0.13 g/mL m-CPBA/DMF solution held for 16 h at 10 °C.
Figure 8. DSC rescanning (test range 0−400 °C) after iso test of 0.13 g/mL m-CPBA/DMF solution at 10 °C.
temperature for 16 h followed by a rescanning test (scan the sample after isoperibolic test from 0 to 400 °C with 4 °C/min heating rate). The isoperibolic test could tell us that at a predefined temperature, with 16 h hold, if safety-relevant energy could be released (considering both the heat release amount and the release rate), then corresponding safety measures should be taken accordingly. The purpose of the rescanning test is to verify the consistency of the isoperibolic test and the scanning test: assume energy released from the scanning test with fresh sample is A J/g, the energy released from isoperibolic test with fresh sample is B J/g, and the energy released from the rescanning test after isoperibolic test is C J/g. Roughly speaking, A should be equal with the sum of B and C. Under the previously optimized conditions (0.13 g/mL and addition of DMF first), the DSC isoperibolic test holding for 16 h was conducted at 60 °C, 10 °C, and 30 °C, respectively. As shown in Figure 5, a decomposition heat of 56 J/g was detected, and 16 J/g energy was detected in the rescanning test (Figure 6), indicating that major energy has been released at 60 °C with 16 h hold (the sum of the results from the isoperibolic test and rescanning test is 72 J/g, which is consistent with the
results of 80 J/g from scanning test with fresh sample in Figure 4). Isoperibolic test at 10 °C showed that no obvious decomposition heat was recorded (Figure 7), and the rescanning test result of 80 J/g heat in Figure 8 further confirmed that at 10 °C with 16 h hold no decomposition occurred. Similar results was obtained for the isoperibolic test at 30 °C (no energy released in the isoperibolic test, and 84 J/g energy was detected during rescanning test; refer to Figures S6 and S7 in the Supporting Material). To leave a larger safety margin for the preparation of m-CPBA/DMF solution, we choose to prepare the solution at 10 °C. It should be noted that the result that no m-CPBA decomposition was recorded within the operation time (16 h) at 10 °C cannot guarantee a long storage time without decomposition. Therefore, it is recommended that the m-CPBA/DMF solution should be prepared and immediately used. Thus, recommended safety measures for preparation of mCPBA/DMF solutions are the following: (1) Control the concentration of m-CPBA in DMF to be
