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Ind. Eng. Chem. Res. 1997, 36, 5302-5306
PROCESS DESIGN AND CONTROL Applying Solubility to the Design and Optimization of a Reaction System D. Michael Hobbs, Paul Schubert, and Hsien-Hsin Tung* Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900
Utilizing the solubility properties of the starting material and product, the reaction yield is significantly enhanced in a system with an undesired consecutive parallel reaction. An excess amount of the starting material is charged at the beginning of the reaction, followed by a partial crystallization of the product during the reaction. The excess unreacted starting material is recovered from the isolated cake by slurry washing and recycling the washing liquors to the next cycle. Through this simple and unique two-filtration recycle process, laboratory and pilotplant data show a yield improvement from 65% of the original process to 72-82%, as well as a significant reduction of raw material usage. Scope To minimize byproduct formation in the design of a reaction system, it is common to adjust the reaction environment such as solvents, temperature, or reagents in order to reduce the rates of side reactions relative to the rate of the desired reaction. Particularly, if the undesired reaction occurs consecutively with the desired reaction as shown in eq 1, it is advantageous to have a high ratio of starting material to product in order to increase reaction selectivity, yield, and product purity [Levenspiel, 1972]. To achieve this goal, one possible approach is to charge an excess amount of starting material at the beginning of the reaction and then recycle the excess unreacted starting material to the next cycle. Another approach is to selectively remove the product from the reaction mixture during the course of the reaction. Selected examples include those from Paul [1990], Tung et al. [1992], and Casey and Liapis [1994]. In this paper, a simple and unique two-filtration recycle process is presented, based upon the difference of solubilities between the starting material and product to optimize the reaction performance. The paper is divided into three sections. In the first section, the fundamental reaction kinetics and crystallization solubility are described. In the second section, the flowsheet of the two-filtration recycle process is proposed. The original nonrecycle process is also included in this section in order to provide a clear comparison. Finally in the third section, experimental results and discussion are presented, together with the conclusion. System Properties Reaction Kinetics. The chemistry of the model system is shown in Figure 1. Reagent A has two equally reactive carbonyl groups. One of these can react with the single methyl group of reagent B to form the * Author to whom correspondence should be addressed. Telephone: 732-594-6686. Fax: 732-594-1310. E-mail: Hsien Hsin
[email protected]. S0888-5885(97)00438-7 CCC: $14.00
condensed product R. Since product R has one remaining reactive carbonyl group, it will further react with the starting material B to form an inert byproduct S. This type of reaction is commonly encountered in the synthesis of pharmaceuticals and can be modeled by a consecutive parallel reaction system as shown in eq 1. k1
A + B 98 R k2
R + B 98 S where A ) starting material isophthalaldehyde (Iso), which contains two reactive carbonyl groups, B ) starting material 7-Chloroquinaldine (7-Chloro), which contains one methyl group, R ) product monoaldehyde (Mono), which contains one reactive carbonyl group, S ) byproduct bis-adduct (Bis), which contains no reacting group and is chemically inert, and k1 and k2 ) rate constants. In this model system, the ratio of k1/k2 is close to 2 [Tung et al., 1992]. As mentioned earlier, a high ratio of A/R is required to ensure a high reaction selectivity for this type of reaction. For convenience and consistency of the presentation, the abbreviated names: Iso, 7-Chloro, Mono, and Bis will be used in place of the generic A, B, R, and S throughout the rest of this paper. Crystallization Solubility. Solubility data of the starting material isophthalaldehyde and product monoaldehyde in one solvent system are presented in Figure 2. It is evident that Iso has a much higher solubility than Mono. The solubility difference between the product and starting material plays a key role in the design of the two-filtration recycle system. A high ratio of Iso over Mono can be maintained by initially charging a large molar excess of Iso and selectively crystallizing the product Mono during the reaction, while the excess Iso remains solubilized in the reaction mixture. Following the reaction, the recovery of excess Iso is further simplified as a result of the solubility difference. After isolating the cake which contains both the product Mono and the unreacted Iso, the excess Iso can be easily recovered in the filtrate after slurry-washing the cake. © 1997 American Chemical Society
Ind. Eng. Chem. Res., Vol. 36, No. 12, 1997 5303
Figure 1. Chemistry.
Figure 2. Solubility.
It should be mentioned that byproduct Bis has a lower solubility than both Iso and Mono. Because Bis is chemically inert, its presence does not affect the reaction performance and its solubility data are not included in this paper. Experiments and Operations Original Process. In order to provide a clear sideby-side comparison with the two-filtration recycle process, the flowsheet of the original process is shown in Figure 3. The operating conditions of the original process are summarized in Table 1. As shown in Figure 3, at the beginning of the batch, the starting materials Iso and 7-Chloro are charged to a reactor. The batch is heated and aged at a reaction temperature above 100 °C. After the reaction is completed, the batch is cooled to approximately 90 °C and the majority of byproduct Bis precipitates. The byproduct slurry is filtered through a dead-end filter to remove the precipitated byproduct Bis. The filtered clear solution is transferred to a crystallizer and slowly cooled to crystallize the product Mono. The product slurry is filtered, and the wet cake is washed and vacuum-dried. The isolated cake contains the product Mono with approximately 4-5 wt % of byproduct Bis.
Figure 3. Flowsheet of the original process.
Recycle Process. The flowsheet of the improved recycle process is shown in Figure 4. The operating parameters are summarized in Table 1. As shown in Table 1, there are two versions of the recycle process. Version I utilizes only a single solvent (toluene). Version II utilizes a binary solvent system (toluene and n-heptane) which further improves the performance of the process. As shown in Figure 4, at the beginning of the batch, the starting materials Iso and 7-Chloro are charged to a reactor. The Iso charged includes the recycled Iso from the previous batch and the fresh Iso. The batch is heated and aged at the desired reaction temperature. After the reaction is completed, the batch is transferred to a crystallizer and cooled over a period of time. Both Mono and the unreacted Iso, along with the byproduct Bis, crystallize at this stage. The hot filtration of byproduct Bis is omitted due to its reduced formation in the recycle process compared to the original process. The slurry is filtered, and the wet cake is washed. The isolated cake contains both Mono and Iso, as well as the byproduct Bis.
5304 Ind. Eng. Chem. Res., Vol. 36, No. 12, 1997
the solid assay, approximately 10 mg of sample was added to a 100 mL volumetric flask and then diluted as per a solution/slurry sample. Standard solutions of individual compounds at a 0.1 mg/mL level were prepared separately to generate response factors for quantitative calculation. Results and Discussion
Figure 4. Flowsheet of the recycle process.
The isolated wet cake after the first filtration is reslurried in a solvent system which dissolves completely the excess Iso and a small amount of Mono. The slurry is filtered, and the wet cake is washed. This isolated cake after the second filtration contains only Mono and Bis, but not Iso. The mother liquors and washes of the second filtration contain all the unreacted Iso. The second filtration mother liquors and washes are concentrated and recycled to the next batch. As indicated earlier, byproduct Bis is not removed in the recycle process, primarily due to a much lower level of formation in comparison to the original process. This does not create any additional complication since Bis is chemically inert and can be easily rejected in the next step of the synthesis, which is not addressed in this paper. There are three key changes made in the recycle process. First, the level of starting material Iso charged at the beginning of the reaction is increased. Up to 3 mol equiv of Iso vs 7-Chloro is charged to the batch versus 1.5 mol equiv charged in the original process. This change significantly increases the reaction selectivity and yield. Second, a slurry wash/filtration operation is included in the recycle process to effectively recover the unreacted Iso. Due to the solubility difference between Iso and Mono, a simple slurry-washing operation recovers all the excess unreacted Iso and reuses it in the next cycle. Third, a binary solvent system is used. The binary solvent system prompts the crystallization of Mono during the reaction and reduces the loss of Mono and Iso in the mother liquor. Analytical Procedures. High-performance liquid chromatography was used to perform the analytical assays, using a Zorbax SB phenyl column (4.6 × 250 mm, 4 × 10-3 mm particle size). The mobile phase was a mixture of acetonitrile and water which contained 0.1 vol % trifluoroacetic acid. A linear gradient elution procedure, starting at 20 vol % acetonitrile and ending at 90 vol % acetonitrile, was applied at an elution rate of 2 mL/min for a period of 15 min. The UV adsorbance was set at 220 nm. For the preparation of a solution or slurry sample, a fixed volume of sample was diluted in a 100 mL volumetric flask, using 50 mL of tetrahydrofuran to solubilize the Bis and then diluting to volume with acetonitrile with a final concentration of approximately 0.1 mg/mL of the interested compounds. For
The experimental results of both the original and recycle processes are listed in Table 2. In the table, the initial mole ratio of Iso/7-Chloro/Mono represents the total charge of Iso, 7-Chloro, and Mono at the beginning of the reaction. The Iso charge includes the fresh Iso and the recycled Iso. The average fresh Iso and recycled Iso are listed for easy comparison. The recycled Iso and Mono at the beginning of the reaction can be found under the column of “second filtration recovery.” Both the reaction yield and the isolated yield are reported in the table. The reaction yield is equivalent to the isolated yield plus mother liquor loss in the first filtration. All percentages reported in this table are based upon the mole equivalent of the 7-Chloro charge except the product purity, which is the weight percentage of product. For example, for the case of a singlesolvent recycle process, the average fresh and recycled Iso charges are 1.55 (155%) and 1.45 (145%) mol equiv of the 7-Chloro charge. The reaction and isolated yields are 80.1% and 72.3% based upon the 7-Chloro charge. The product purity is 87% by weight, i.e., 0.87 g of Mono/g of product. The first filtration losses of Mono and Iso are 7.6% and 55.2% mole equiv of the 7-Chloro charge. The second filtration recoveries of Mono and Iso are 21.0% and 145% (1.45) mol equiv of the 7-Chloro charge. Reaction Yield. As shown in Table 2, the average reaction yield is only 72.2% for the original process. The reaction yield is 79.9% for the single-solvent recycle process and is 84.3% for the mixed-solvent recycle process. The improvement of the reaction yield is 7.7% and 12.1%, respectively. In the single-solvent recycle process, the increase in the reaction yield is a direct result of increasing the Iso/ 7-Chloro ratio from 1.5:1 to 3:1, which effectively increases the ratio of Iso/Mono during the reaction. This change produces the ∼8% yield improvement for the single-solvent recycle process relative to the original process. In the mixed-solvent recycle process, two additional factors help to improve the reaction yield even further. The first factor is the crystallization of Mono during the reaction. It should be pointed out that due to the difficulty of sampling and filtration of slurry at the reaction temperature, the solid phase cannot be easily assayed to quantify the percentage of Mono present. The second factor that improves the reaction yield in the mixed-solvent recycle process is that less Mono is recycled (13% mol equiv) than in the single-solvent recycle process (21% mol equiv). The reduction of recycled Mono is realized as a result of a better operational control of slurry washing temperature and cake washing. Isolated Yield. As shown in Table 2, the isolated yields of the recycle process are 72.3% and 82.2%, respectively, versus the isolated yield of the original process of 66.1%. As discussed above, the improvement is primarily due to three factors, all of which contribute to a higher reaction yield: (1) higher ratio of Iso/Mono, (2) Mono crystallization, and (3) less recycled Mono.
Ind. Eng. Chem. Res., Vol. 36, No. 12, 1997 5305 Table 1. Operating Parameters recycle reaction Iso/7-Chloro/Mono (mole ratio)a solvent amount, mL/g of 7-Chloro n-heptane/toluene volume ratio n-butyl acetate (%) temperature (°C) reaction age (h) hot filtration temperature (°C) crystallization additional solvent charge amount, mL/g of 7-Chloro n-heptane/toluene volume ratio n-butyl acetate (%) charge time (h) charge temperature (°C) cooling time (h) final cooling temperature (°C) first filtration wash solvent amount, mL/g of 7-Chloro n-heptane/toluene, volume ratio n-butyl acetate (%) temperature (°C) second filtration solvent amount, mL/g of 7-Chloro n-heptane/toluene volume ratio slurry time (h) temperature (°C) wash solvent amount, mL/g of 7-Chloro n-heptane/toluene volume ratio a
original
single solvent
1.5/1/0
3/1/0.2
3/1/0.12
6.4 n/a 100 138 10 yes 95
6.1 0/100 n/a 120 10-12 no
6.4 75/25 n/a 99-101 13 no
0.53 n/a 100 1 90 10 15
3.2 0/100 n/a 1 85 10 -15
12.8 75/25 n/a 2 80-99 6-8 0
2.7 n/a 100
2.7 0/100 n/a -15 yes
10 75/25 n/a 0 yes
16 0/100 1-2 ambient (25)
22 0/100 1-2 19-21
16 0/100
10 0/100
no
mixed solvents
1.5 mol equiv of acetic anhydride was charged in all processes as the activating agent.
Table 2. Experimental Results
process original
isolated yield (%)
reaction yield (%)
product purity (wt %) Mono
1st filtration loss (%)
2nd filtration recovery (%)
Mono
Iso
Mono
(1.5 + 0)/1/0
64.4 66.7 67.4 66.1
69.6 73.2 73.9 72.2
94.7 97.6 95.6 96.0
5.2 6.5 6.5 6.1
35.3 44.0 48.4 42.6
n/a n/a n/a n/a
4 5 6 7 8
3/1/0 3/1/0.19 3/1/0.16 3/1/0.24 3/1/0.21 (1.55 + 1.45)/1/0.21
58.1 76.6 68.1 72.0 72.4 72.3
82.7 80.6 82.1 76.1 81.6 80.1
88.9 88.0 87.6 85.1 87.4 87.0
6.6 7.1 7.9 7.6 7.8 7.7
65 66 55 57 43 55.2
19 16 24 21 23 21.0
142 126 154 131 169 145
169/170 176/177 178/179 180/181 184/185 190/191
3/1/0.15 3/1/0.09 3/1/0.14 3/1/0.13 3/1/0.13 3/1/0.13 (1.22 + 1.78)/1/0.13
80.6 83.5 81.6 82.9 82.4 82.1 82.2
82.7 85.0 83.9 84.9 84.7 84.4 84.4
89.7 90.0 90.2 88.7 89.7 91.0 89.7
2.1 1.5 2.3 2.0 2.3 2.3 2.1
21.2 20.8 24.3 19.0 20.7 20.2 21.2
9 13.5 12.8 14.0 13.8 14.9 13.0
163 188 150 204 186 175 178
batch no. 1 2 3
average recycle (single solvent)
average recycle (mixed solvent)
average a
initial mole ratio (fresh + recycled Iso)/ 7-Chloro/Mono 1.5/1/0
Iso
For the single-solvent recycle process, batch 4 was excluded in the average calculation.
Moreover, by examining the data closely, a reduction of the first filtration loss in the mother liquor in the mixed-solvent recycle process is revealed. As shown in Table 2, less R (Mono) is lost in the first filtration (2.1% vs 6.1% and 7.6%). The introduction of n-heptane enhances the isolated yield not only by influencing the reaction yield but also by reducing mother liquor losses of Mono and Iso. It should be pointed out that the amount of n-heptane charged needs to be carefully balanced against the effective rejection of impurities and the reduction of
mother liquor loss of Iso and Mono, since n-heptane reduces the solubilities of all components including impurities. In addition, a second liquid phase was present during the reaction at a high level of n-heptane. The optimal percentage of n-heptane was found to be 75% after including all these criteria. Raw Material A (Iso) Requirement. As shown in Table 2, the fresh charge of raw material Iso for each process is 1.5, 1.55, and 1.22 equiv vs 7-Chloro, respectively. The excess charge of raw material Iso is reduced from 50% in the original process to 22% in the new
5306 Ind. Eng. Chem. Res., Vol. 36, No. 12, 1997
process. In the recycle process, the main loss of excess Iso is in the first filtration mother liquors. Upon Introduction of n-heptane as the antisolvent, the percentage of Iso lost in the mother liquors is reduced from 42.6% in the original process to 21.2% in the mixedsolvent recycle process. Since Iso is a key component of the overall process cost, the reduction of Iso requirement provides a substantial savings. Conclusions A simple and unique two-filtration process was presented that takes advantage of the solubility difference between the starting material and product to enhance reaction selectivity in a competitive consecutive reaction sequence. By charging an excess amount of the starting material at the beginning of reaction, followed by a partial crystallization of product during the reaction, the reaction selectivity and yield are significantly improved. Recovery of the excess unreacted starting material is easily accomplished by slurry washing the cake and recycling the filtrate to the next cycle. Laboratory and pilot-plant data show a yield improvement from 65% of the original process to 82% of the improved
recycle process, as well as a significant reduction of raw material usage. Literature Cited Casey, J. T.; Liapis, A. I. Fixed Bed Sorption with Recycle, Part III: Consecutive Reversible Reactions. Chem. Eng. Res. Des. 1985, 63, 398. Levenspiel, O. Chemical Reaction Engineering; John Wiley & Sons: New York, 1972. Paul, E. L. Reaction Systems for Bulk Pharmaceutical Production. Chem. Ind. 1990, May, 21. Tung, H.-H.; Hobbs, D. M.; Paul, E. L. Reaction System Design with Solid Precipitation. AIChE Annual Meeting, Nov 1992.
Received for review June 16, 1997 Revised manuscript received September 5, 1997 Accepted September 5, 1997X IE970438G
X Abstract published in Advance ACS Abstracts, November 1, 1997.
